A MELANOSOMAL MEMBRANE-PROTEIN IS A CELL-SURFACE TARGET FOR MELANOMA THERAPY

Differentiation antigens on cancer cells are recognized by the immune system, A prototype set of these autoantigens in melanoma cells are th e melanosomal glycoproteins, expressed in both melanomas and normal me lanocytes, These are intracellular proteins that can be recognized by both antibodies and T lymphocytes, While one can understand how T cell s can respond to intracellular proteins, based on cellular requirement s for antigen processing and presentation, it is more difficult to und erstand how antibody responses to melanosomal proteins could lead to t umor rejection, We demonstrate that gp75 is expressed on the cell surf ace as well as intracellularly in human and mouse melanomas, The surfa ce expression of gp75 can be augmented by IFN-gamma and during tumor g rowth ill vivo, Surface expression of gp75 on mouse melanoma cells cor relates with the ability of a monoclonal antibody (mAb) against gp75 t o reject melanomas in syngeneic mice, Antibody-mediated rejection seem s to require the Fc portion of the antibody, suggesting a role for Fc receptor-positive effector cells such as natural killer cells, However , although NK1.1(+) cells have been implicated in antibody-induced rej ection in vivo, cell surface expression of gp75(+) on melanoma does no t lead to susceptibility to antibody-dependent cellular cytotoxicity i n vitro, The mAb to gp75 induced tumor rejection in mice carrying both sold and bg/bg traits, showing that neither thymus-dependent T cells nor natural killer cytotoxic activity was required in vivo, Long-term treatment of mice with mAb led to patchy depigmentation in the coat. I n summary, an intracellular organellar protein can be expressed at the cell surface and provide an antigenic target for antibody therapy and autoimmunity.